Polymeric bone foam composition and method

ABSTRACT

Biomaterials, in particular bone foams, a process for preparing such materials as well as an applicator for applying the biomaterials directly to the patient&#39;s application site, and the use of a composition comprising water, a surfactant and a propellant in the preparation of a bone foam for the preparation of a calcium phosphate foam wherein the foam is obtainable by the mixture of at least two phases, a first phase comprising water and optionally a propellant, a second phase comprising one or more sources for calcium and/or phosphate, and wherein the foaming is performed during the mixture of the at least two phases to provide an improved calcium phosphate foam, process for the preparation of a calcium phosphate foam, use of a composition, solid state structure, calcium phosphate cement foam and bone foam applicator.

FIELD OF THE INVENTION

The present invention is related to new biomaterials, in particular bonefoams, a process for preparing such materials as well as an applicatorfor applying the biomaterials directly to the patient's applicationsite. Further, the present invention is directed to the use of acomposition comprising water, a surfactant and a propellant in thepreparation of a bone foam.

BACKGROUND OF THE INVENTION

The natural capability of the human body to regenerate bone defects isnot sufficient. Therefore, for the human body is typically not possibleto restore a fracture on its own. Medical implants are useful inproviding sufficient stability for the fracture and support the curingprocess.

In cases where the bone damage is too severe, bone cements may also beapplied to stabilize implants and thereby support the curing of thedefect.

Bone cements may act as an artificial “linker” between the natural boneand the implant. Usually, bone cements are classified into two generalclasses, so called PMMA bone cements (Poly Methyl Methacrylates) andcalcium phosphate based cements.

Since the discovery of the calcium phosphate based cements in the mid1980ies, various formulations have been developed. The underlyingprinciple of these materials is that a mixture of one or more calciumsalts with water or an aqueous solution forms a cement which due to adissolution and precipitation process sets. The setting typically takesplace under physiological conditions. The final reaction product (aftersetting) is typically a hydroxyapatite that is very similar to thebiological material in terms of crystallinity and non-stoichiometry.

One of the main advantages of the calcium phosphate foams is theirexcellent biocompatibility and bioactivity. Moreover, the foam iscapable of adapting to the geometry of the defect.

The properties of the resulting calcium phosphate foam (bone foam) canbe adjusted by modifying various parameters such as the chemicalcomposition of the starting material, the relative proportion of theconstituents, additives (such as seeds, accelerants, retardants, etc.),particle size, pH value, liquid to powder ratio, temperature, humidty orthe like.

The porosity of the bone foam is a further important parameter and isalso important for the durability of e.g. implants. On the one hand, ahigh porosity is desired to allow for space for newly formed bonetissue. On the other hand, the higher the porosity of the resultingmaterial, the smaller is its breaking strength.

Moreover, the handling of the current products is far from ideal. Theapplication of bone cements into a void for example of an osteoporoticbone is very difficult as the cement paste is made outside theapplication site and subsequently applied into the damaged bone.Therefore, it is very difficult to apply the foam into small cavitieswhich cannot be reached by the instrument with which the paste isapplied to the damaged bone.

EP 1 787 626 describes an injectable self setting calcium phosphate foamfor use as biomaterial. The foam is prepared by agitation and mechanicalwhipping and may subsequently be applied.

Particles for incorporation of particulate components in a calciumphosphate cement are for example known from U.S. Pat. No. 5,525,148issued to Chow et al., U.S. Pat. No. 5,820,632 issued to Constantz etal., or JP 5,023,387 issued to Hirano et al.

One of the problems associated with the calcium phosphate bone foams ofthe prior art is that they are prepared extra corporally and only afterpreparation applied to the corresponding site of application in the bodyby manually controlled means, e.g. a syringe. For small applicationsites or complex geometric forms there is a need for an improvedapplication of the foams and / or foams which are instantly applied tothe application site after preparation (“direct to patientapplication”).

SUMMARY OF THE INVENTION

It would be desirable to provide an improved calcium phosphate foam,process for the preparation of a calcium phosphate foam, use of acomposition, solid state structure, calcium phosphate cement foam andbone foam applicator.

The invention provides calcium phosphate foam, process for thepreparation of a calcium phosphate foam, use of a composition, solidstate structure, and calcium phosphate cement foam and a bone foamapplicator according to the subject matter of the independent claims.Further embodiments are incorporated in the dependent claims.

According to an exemplary embodiment of the invention, there is provideda process for the preparation of a calcium phosphate foam wherein thefoam is obtainable by the mixture of at least two phases, a first phasecomprising water and a second phase comprising one or more sources forcalcium and/or phosphate, and wherein the foaming is performed duringthe mixture of the at least two phases. The first and/or the secondphase may optionally further comprise a propellant. The term “during themixture” of the at least two phases should be understood that thefoaming of the cement starts just before, immediately when orsubstantially immediately when the first and the second phases are beingcontacted.

Thus, the process may provide a bone foam which is foamed in situ whilemixing the first and the second phase so that no sequential foaming ofthe mixed cement paste or any precursors thereof is required any more.The optional propellant may be used for foaming the respective first andsecond phase.

According to another exemplary embodiment of the invention, the use of acomposition comprising water, a surfactant and a propellant in thepreparation of a calcium phosphate foam is provided, wherein thecomposition is contacted with at least one phase comprising one or moresources for calcium and/or phosphate.

Thus, the use of the composition allows for an in-situ foaming of thecement paste which is obtained upon mixing of the composition comprisingwater and the one or more sources for calcium and/or phosphate by thepropellant, so that no additional step of foaming of the cement paste isrequired.

According to another exemplary embodiment of the invention the calciumphosphate foam obtainable by the above described process for use in boneregeneration, tissue engineering or as a bone substitute is provided.

According to an exemplary embodiment of the invention the solid statestructure obtainable by the above described process after setting of thefoam is provided. A solid state structure for use in bone surgery, boneregeneration, bone defect fillings, stabilization of bone fractures,fixing of implants, tissue engineering or as a bone substitute is alsoprovided.

According to an exemplary embodiment of the invention there is provideda bone foam applicator, comprising a first container for storing a firstcomposition having a first outlet, a second container for storing asecond composition having a second outlet, a mixing arrangement having afirst inlet and a second inlet, and an application outlet, an activationunit, wherein the first outlet is connected to the first inlet, and thesecond outlet is connected to the second inlet, wherein the activationunit is adapted to activate a convey of the first composition from thefirst container and the second composition from the second container tothe mixing arrangement, wherein the mixing arrangement comprises amixing volume being connected to the first inlet, the second inlet andthe application outlet, wherein the mixing volume being adapted formixing the first composition and the second composition within themixing volume for foaming the mixed first composition and secondcomposition when exiting the application outlet.

Thus, a bone foam applicator may be provided by which the firstcomposition and the second composition may be mixed within the mixingvolume before exiting the bone foam applicator. This allows a sufficientand reliable mixing process, in particular for medical compositions,like for example bone foam cement. In a medical application a reliablemixing process is of utmost importance, as for example bone foam cementis used during larger surgeries requiring save and reproducibleprocesses. As a rule, the mixing process does not require further itemsor tools, as the mixing takes place within the bone foam applicator,i.e. within a mixing volume. This further allows providing the bone foamapplicator as a simple single or multiple use device, which the surgeonmay take from a storage when required during the surgery. In additionthe first and second composition may be compositions which are activatedwhen being mixed, so that this activation may take place on demand whenapplying the bone foam to the application site. Before activation, thecompositions may be stored, without being activated. It should be notedthat also more than two composition may be used, which as a rulerequires more than two containers.

According to an exemplary embodiment of the invention at least one ofthe first container and the second container are adapted to store apropellant for blowing out the respective first and second compositions.

Thus, no further drive is required for conveying the mixture of thefirst and second composition. The bone foam applicator may be designedsuch that only a low force application is required for activation.

According to an exemplary embodiment of the invention the activationunit is integrally formed with the mixing arrangement and adapted toactivate at least one valve positioned in the respective first andsecond outlet of the respective first and second container.

Thus, the number of movable parts may be reduced. A reduced number ofmovable parts as a rule lead to a higher reliability of the entiredevice.

According to an exemplary embodiment of the invention, the firstcontainer comprises water and optionally a propellant, and the secondcontainer comprises one or more sources for calcium and/or phosphate.

Thus, the bone foam may be obtained in situ by activation the bone foamapplicator. The water from the first container and the sources forcalcium and/or phosphate from the second container each enter the mixingvolume. Within the mixing volume the bone foam will be generatedin-situ. The generated bone foam may exit the mixing volume via theapplication outlet so that the bone foam may be directly applied to thepatient's application site, when directing the application outletdirectly to the patient's site. The application outlet may be providedwith an extension like a tube or a conduit for an easier application.The tip of the application exit or the extension may be provided with anapplication head. The application head may have a plurality of openingsand/or nozzles each pointing into different directions. The finalizationof the chemical process of foam generation may also take place at thepatient's site, i.e. at least a part of the chemical reaction, the finalexpansion and/or the hardening of the bone foam.

It should be noted that the above features may also be combined. Thecombination of the above features may also lead to synergetic effects,even if not explicitly described in detail.

These and other aspects of the present invention will become apparentfrom and elucidated with reference to the embodiments describedhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments of the present invention will be described in thefollowing, at least a part of it with reference to the followingdrawings.

FIG. 1 illustrates a bone foam applicator in parts with a front outputorifice according to an embodiment of the invention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

According to an exemplary embodiment of the invention, there is provideda process for the preparation of a calcium phosphate foam wherein thefoam is obtainable by the mixture of at least two phases, a first phasecomprising water and a second phase comprising one or more sources forcalcium and/or phosphate, and wherein the foaming is performed duringthe mixture of the at least two phases. The first phase may optionallyfurther comprise a propellant. The second phase may also optionallyfurther comprise a propellant.

In one preferred embodiment of the invention, the first phase furthercomprises a propellant which allows for the foaming of the first and thesecond phase when the at least two phases are mixed. Upon mixing of theat least two phases, the cement paste is formed by the reaction of thefirst phase comprising water and the second phase comprising one or moresources of calcium and/or phosphate. The in-situ foaming of the cementpaste formed from the at least two phases allows for the omission of anadditional foaming step (e.g. performed by mechanical agitation)required by cement pastes described in the art.

In another exemplary embodiment of the invention, the first phasefurther comprises a stabilizing agent. The stabilizing agent supportsthe bubbles formed during foaming and thereby allow for a preparation ofsolid state structures exhibiting a higher macroporosity. A highmacroporosity of the resulting solid state structure is desirable forbone regeneration and further conditions of interest of the presentinvention since it facilitates angiogenesis.

The stabilizing agent is preferably biocompatible.

The stabilizing agent is preferably selected from the group consistingof a surfactant, gelling agents, soluble phosphate salts, organic acids,and any mixtures thereof and more preferably is a surfactant.

The surfactant may be selected from the group consisting of a cationic,anionic or non-ionic surfactant and is preferably a non-ionicsurfactant. In an alternative preferred embodiment of the presentinvention, the surfactant is a polymeric surfactant.

The surfactant that may be applied in the present invention are selectedfrom the group consisting of substituted polyethylenglycols, PEGylatedfatty acid derivatives, PEGylated glycerol fatty acid derivatives,PEGylated sorbitan fatty acid derivatives, and polypropyleneglycol-PEG-blockpolymers derivatives and is preferably selected from thegroup consisting of PEG-glycerol rizinoleate,PEG-gycerol-hydroxystearate, polypropylene glycol-PEG-blockpolymer,PEG-hydroxystearate, and PEG-sorbitan-monooleate. In particluar,PEG-35-glycerol rizinoleates, PEG-40-gycerol-hydroxystearates,PEG-15-hydroxystearates, PEG-20-sorbitan-monooleates are preferred.Suitable surfactants that may be applied in the present invention arefor example Cremophor EL®, Cremophor RH400®, Poloxamer 188®, Solutol HS15®, or Tween 80®.

In case a stabilizing agent is present in the first composition, thestabilizing agent is present between 0.1% and 10% by weight, 0.5% to7.5% or 0.5% to 3% based on the first phase. In a preferred embodiment,wherein the stabilizing agent is a surfactant, the surfactant is presentbetween 0.1% and 10% by weight, 0.5% to 7.5% or 0.5% to 3% based on thefirst phase.

In an exemplary embodiment of the invention, the first phase furthercomprises a propellant. The propellant may be selected from the groupconsisting of propane, butane, iso-butane, heptafluorpropane,pentafluorobutane, and tetrafluoroethan and any mixtures of theforegoing. In a preferred embodiment, the propellant may be presentbetween 5% and 25% by weight/weight based on the first phase.

The properties of foam may also be adjusted by the vapor pressure of thepropellant in the first phase. In a preferred embodiment of theinvention, the vapor pressure of the propellant is from about 1.1 toabout 8 bar, preferably from about 1.3 to about 6 bar, and morepreferably from about 1.5 to about 5 bar.

The compositions of the present invention may further comprisecomponents selected from the group consisting of binders, accelerators,cohesion promotors, and any mixtures of the foregoing.

Binders suitable for use in the present invention are selected from thegroup consisting of sodium alginate, hydroxypropyl methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxyethyl starch, soluable starch, cyclodextrin, dextran sulphate,polyvinylpyrrolidone, chitosan, hyaluronic acid and any mixtures of theforegoing. The binders are preferably present in the range from 0.1% to10% by weight, more preferably from 0.5% to 5% by weight based on thefirst phase. Polyvinylpyrrolidone is preferred.

Accelerators of the setting reaction may be selected from the groupconsisting of Na₂HPO₄, NaH₂PO₄, tri-sodiumcitrate-dihydrate, KH₂PO₄, orK₂HPO₄ or any mixtures thereof. Preferably, the accelerator is presentin the range from 0.1 to 10% (by weight), preferably in the range from0.5% to 5% based on the first composition.

The reagents of the second phase of the cement include a source ofcalcium and a source of phosphate, which can be present as a singlecomponent or as two or more components. In case of a single source bothcalcium and phosphate are comprised therein. In case two or morecomponents are applied as the source for calcium and/or phosphate,either each of them comprises calcium and phosphate or the sources forcalcium and phosphate are present in separate components. The secondphase comprises a calcium and/or a phosphate source selected from thegroup consisting of

-   -   a) at least a source of calcium and/or phosphate selected from        tetracalcium phosphate, dicalcium phosphate anhydride, dicalcium        phosphate dihydrate, alpha tricalcium phosphate, beta tricalcium        phosphate, monocalcium phosphate monohydrate, hydroxyapatite,        calcium deficient hydroxyapatite, fluorapatite, amorphous        calcium phosphate, calcium- sodium- and potassium-phosphate,        calcium- and sodium- phosphate, calcium- and        potassium-phosphate, and calcium pyrophosphate; or        alternatively,    -   b) at least a compound of calcium selected from calcium        carbonate, calcium sulphate, calcium sulphate hemi hydrate,        calcium oxide, and calcium hydroxide, and at least a compound of        phosphate selected from phosphoric acid and all the soluble        phosphates; or alternatively    -   c) a mixture of at least a compound defined in option a) and at        least a compound defined in option b).

From these sources of calcium and/or phosphate tetracalcium phosphate,dicalcium phosphate anhydride, dicalcium phosphate dihydrate, alphatricalcium phosphate, beta tricalcium phosphate, monocalcium phosphatemonohydrate, hydroxyapatite, calcium deficient hydroxyapatite,fluorapatite, amorphous calcium phosphate, calcium- sodium- andpotassium-phosphate, calcium- and sodium-phosphate, calcium- andpotassium-phosphate, and calcium pyrophosphate are preferred.

Even more preferably, the second phase comprises tetra-calciumphosphate, di-calciumphosphate or mixtures thereof, and preferably theratio of tetra-calcium phosphate to di-calciumphosphate is between 1:5and 5:1 and more preferably between 1:3 and 3:1. A suitable source forcalcium and/or phosphate is e.g. the mixture of dicalcium phosphatedihydrate, tetracalcium phosphate comprising tri-sodium citrate soldunder the tradename “HydroSet®” by Stryker®.

In a further preferred embodiment of the invention, the particle size ofthe calcium and/or phosphate source is in the range of 0.05 to 100 μm,and preferably is between 0.1 and 75 μm, more preferably is between 0.2and 50 μm, and even more preferably between 0.5 and 10 μm.

The particle size distribution is determined by methods known to theperson skilled in the art such as laser diffraction or photoncorrelation spectroscopy. In general, laser diffraction is used whendetermining particle size distribution of particles about 0.5 μm orlarger. For example suitable apparatus such as a laser diffractometer“Helos” of the company Sympatec may be used. Photon correlationspectroscopy is applied for particle size distribution of 5 μm or less.A suitable apparatus for Photon correlation spectroscopy is the MalvernZetasizer Nano-ZS. Particle size distributions between 0.5 μam and 5 μmmay be analyzed by either of the two methods described above.

In a further exemplary embodiment of the invention, the second phase maypreferably comprise a further component selected from the groupconsisting of an alcohol, a propellant, and any mixtures thereof.

The foam prepared by the process of the present invention may comprisean active agent (such as anticancer agents, antibiotics and/orantioxidans), a viable cell, or a growth factor or a combination of theforegoing. Preferably, these additional components are added in form ofa solution or suspension. The use of an osteoblast suspension ispreferred.

The process of the present invention allows for an in situ preparationof the bone foam. Thus, the foaming starts immediately when the firstand the second phase are mixed. After formation of the foam it sets inless than 60 min, less than 50 min, less than 40 min, less than 30 min,less than 15 min, less than 10 min, less than 8 min, or less than 5 minat 37° C.

In an exemplary embodiment of the present invention, the ratio of thefirst phase and the second phase is between 10:1 and 1:10, andpreferably between 8:1 and 1:8, and even more preferably 5:1 and 1:5.

The calcium phosphate foam according to the present invention comprisescalcium phosphate cement and at least one stabilizing agent.

The stabilizing agent is preferably selected from the group consistingof a surfactant, gelling agents, soluble phosphate salts, organic acids,and any mixtures thereof and more preferably is a surfactant.

Suitable soluble phosphate salts are preferably selected from the groupconsisting of primary phosphates (dihydrogen phosphates), secondaryphosphates (hydrogen phosphates) and tertiary phosphates, preferablyalkaline or alkaline earth phosphates such as NaH₂PO₄, KH₂PO₄ ,Na₂HPO_(4,) K₂HPO₄₅ Na₃PO₄, or K₃PO₄.

Suitable organic acids are preferably selected from the group consistingof organic acid selected from oxalic acid, acetic acid, formic acid,malic acid, maleic acid, malonic acid, succinic acid, fumaric acid,phthalic acid, terephthalic acid, citric acid, tartaric acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,trifluoroacetic acid, ascorbic acid, fatty acids and the like. Citricacid is preferred.

The surfactant may be selected from the group consisting of a cationic,anionic or non-ionic surfactant and is preferably a non-ionicsurfactant. In an alternative preferred embodiment of the presentinvention, the surfactant is a polymeric surfactant. With respect to thepreferred surfactants, it is referred to the above mentioned preferredsurfactants.

The calcium phosphate foam according to the present invention haspreferably a viscosity which allows for a direct application of thecalcium phosphate foam to the application site e.g. with the applicatorof the present invention described above. The calcium phosphate foam iscapable of being applied to and fill small cavities before setting. Theviscosity of the calcium phosphate foam of the present invention (nonhardened) is between 100 and 100.000 cP at 20° C.

Calcium phosphate foam of the present invention exhibits (after setting)a macroporosity in the range of 5 to 90 vol.-%, preferably in the rangeof 15 to 80 vol.-%, more preferably between 20 and 80%, even morepreferably between 25 and 80 vol.-% and more preferably 30 and 80%, andmost preferably between 35 and 80%. Said set foam (a solid statestructure) comprises pores having a diameter comprising between 10 and1000 μm, preferably between 100 and 800 μm. The size of the pores may beadjusted by various parameters such as the concentration of thestabilizing agent or the particle size of the calcium and/or phosphatesources.

Preferably the macropores are interconnected. Interconnectivity of thepores may be induced by the foaming process. However, theinterconnectivity of the pores may be increased by measures known to theskilled person such as incorporation of particulate components in thesecond phase. These particulate components should be insoluble in thecement but dissolve after being exposed to physiological conditionsafter the cement foam has set. Such particles are for example mentionedin U.S. Pat. No. 5,525,148 issued to Chow et al., U.S. Pat. No.5,820,632 issued to Constantz et al., or JP 5,023,387 issued to Hiranoet al., all incorporated herein by reference.

Preferably the calcium phosphate foam of the present invention exhibitsa setting time measured by the Gillmore needles method less than 45 min,less than 35 min, less than 25 min, less than 15 min, less than 10 min,less than 8 min, or less than 5 min. Alternatively, a Zwick/RoellMaterialpriffer Z2.5 may also be applied for determination of thesetting time.

In a further exemplary embodiment, the calcium phosphate foam preferablyis stable for at least 15 min, at least 30 min, at least 40 min, atleast 45 min, at least 50 min, or at least 60 min. The stability of thefoam is measured by the so called “cylinder method”, in which ameasuring cylinder is filled with foam and by determination of therespective foam and liquid volume at specific time points, the stabilityof the foam is determined. If the stability of the foam is sufficient,the foam sets in the foamed structure to form a corresponding solidstate structure.

In a further exemplary embodiment of the invention, the calciumphosphate foam is self setting, preferably under physiologicalconditions (e.g. temperature, aqueous environment).

In yet another exemplary embodiment of the invention, the foam furtherpreferably comprises a crosslinking agent. The crosslinking agentassists in the setting of the foam.

A further aspect of the present invention is directed to a use of acomposition comprising water, a surfactant and a propellant in thepreparation of a calcium phosphate foam comprising contacting saidcomposition with at least one phase comprising one or more sources forcalcium and/or phosphate. The use of the composition comprising water, asurfactant and a propellant allows for an in-situ foaming of the cementpaste, once the composition has been brought in contact with one or moresources for calcium and/or phosphate. Thereby no additional foaming stepof either the first or the second phase or the cement paste is requiredany more.

Suitable surfactant and propellants for the use have been describedabove.

The solid state structure and the calcium phosphate foam of the presentinvention may be used in bone surgery, bone regeneration, bone defectsfilling, stabilization of bone fractures, fixing of prostheses orimplants, and tissue engineering scaffolds.

FIG. 1 illustrates a bone foam applicator with a front output orificeaccording to an embodiment of the invention. The bone foam applicatorcomprises a first container 10 for storing a first composition and asecond container 20 for storing a second composition. Both containerseach have an outlet 11, 22. The applicator further comprises a mixingarrangement 30 having a first inlet 31 and a second inlet 32, and anapplication outlet 33. The first outlet is connected to the first inlet,and the second outlet is connected to the second inlet. The mixingarrangement serves for mixing the first and second composition. Themixing process may be activated by an activation unit 40. The activationunit is adapted to activate a conveyance of the first composition fromthe first container and the second composition from the second containerto the mixing arrangement. The mixing arrangement comprises a mixingvolume 34 being connected to the first inlet, the second inlet and theapplication outlet, wherein the mixing volume is adapted for mixing thefirst composition and the second composition within the mixing volumefor foaming the mixed first composition and second composition whenexiting the application outlet. The containers 10, 20 may be stored in afirst housing part. The mixing arrangement 30 may movably located to thefirst housing part 51, such that a second housing part 52 may cover thecontainers 10, 20 and the mixing arrangement 30. An activating element40 in form of a push button may serve as a lever to push down the entiremixing arrangement 30 to set free the both compositions from therespective container 10, 20.

In all described devices the first container may comprise water andoptionally a propellant, and the second container may comprise one ormore sources for calcium and/or phosphate. Thus, the bone foam may beobtained in situ by activation the bone foam applicator. The water fromthe first container and the sources for calcium and/or phosphate fromthe second container each may enter the mixing volume. Within the mixingvolume the bone foam will be generated in-situ. The generated bone foammay exit the mixing volume via the application outlet so that the bonefoam may be directly applied to the patient's application site, whendirecting the application outlet directly to the patient's site. Theapplication outlet may be provided with an extension like a tube or aconduit for an easier application (not shown). The tip of theapplication exit or the extension may be provided with an applicationhead (not shown). The application head may have a plurality of openingsand/or nozzles each pointing into different directions. This allows abetter distribution of the applied foam. The finalization of thechemical process of foam generation may also take place at the patient'ssite, i.e. at least a part of the chemical reaction, the final expansionand/or the hardening of the bone foam.

It has to be noted that embodiments of the invention are described withreference to different subject matters. In particular, some embodimentsare described with reference to method type claims whereas otherembodiments are described with reference to the device type claims.However, a person skilled in the art will gather from the above and thefollowing description that, unless otherwise notified, in addition toany combination of features belonging to one type of subject matter alsoany combination between features relating to different subject mattersis considered to be disclosed with this application. However, allfeatures can be combined providing synergetic effects that are more thanthe simple summation of the features. It has to be noted that exemplaryembodiments of the invention are described with reference to differentsubject matters. In particular, some exemplary embodiments are describedwith reference to apparatus type claims whereas other exemplaryembodiments are described with reference to method type claims. However,a person skilled in the art will gather from the above and the followingdescription that, unless other notified, in addition to any combinationof features belonging to one type of subject matter also any combinationbetween features relating to different subject matters, in particularbetween features of the apparatus type claims and features of the methodtype claims is considered to be disclosed with this application. In theclaims, the word “comprising” does not exclude other elements or steps,and the indefinite article “a” or “an” does not exclude a plurality. Themere fact that certain measures are re-cited in mutually differentdependent claims does not indicate that a combination of these measurescannot be used to advantage.

REFERENCE LIST

-   10 first container-   11 first outlet-   20 second container-   22 second outlet-   30 mixing arrangement-   31 first inlet-   32 second inlet-   33 application outlet-   34 mixing volume-   40 activation unit-   51 first housing part-   52 second housing part

1. A process for preparing a calcium phosphate foam comprising: mixinga) a first phase comprising water, propellant, and a stabilizing agent,and b) a second phase comprising one or more sources for calcium and/orphosphate, and initiating foaming during the mixing of the first andsecond phases.
 2. (canceled)
 3. (canceled)
 4. The process of claim 1,wherein the stabilizing agent is selected from the group consisting of asurfactant, gelling agent, soluble phosphate salts, organic acids, andany mixtures thereof.
 5. The process of claim 4, wherein the surfactantis at least one of (i) a cationic, anionic or non-ionic surfactant; (ii)a polymeric surfactant; (ii) PEGylated fatty acid derivatives, PEGylatedglycerol fatty acid derivatives, PEGylated sorbitan fatty acid, andpolypropylene glycol-PEG-blockpolymer derivatives and preferably isselected from the group consisting of PEG-35-glycerol rizinoleate,PEG-40-gycerol- hydro xystearate, polypropylene glycol-PEG-blockpolymer,PEG-15-hydroxystearate, or PEG-20-sorbitan-monooleate.
 6. (canceled) 7.(canceled)
 8. The process of claim 4, wherein the surfactant is presentbetween about 0.1% and about 10% by weight based on the first phase. 9.The process of claim 1, wherein the propellant in the first phase isselected from the group consisting of propane, butane, iso-butane,heptafluorpropane, pentafluorobutane, and tetrafluoroethan and anymixtures of thereof, and is present between about 5% and about 25% byweight/weight based on the first phase.
 10. (canceled)
 11. The processof claim 1, wherein the first phase is formulated with a vapor pressureof the propellant of about 1.1 to about 8 bar.
 12. The process of claim1, wherein the first phase further comprises at least one componentselected from the group consisting of binders, accelerators, cohesionpromoters, and any mixtures of the foregoing, wherein the binder ispolyvinylpyrrolidone and the accelerator is Na₂HPO₄, NaH₂PO₄,tri-sodiumcitrate dihydrate, KH₂PO₄, or K₂HPO₄ or any mixtures thereof;and the second phase further comprises a component selected from thegroup consisting of an alcohol, a propellant, and any mixtures thereof.13. The process according to claim 1, wherein the second phase comprisesa calcium and/or a phosphate source selected from the group consistingof a) at least a source of calcium and/or phosphate selected from thegroup consisting of tetracalcium phosphate, dicalcium phosphateanhydride, dicalcium phosphate dihydrate, alpha tricalcium phosphate,beta tricalcium phosphate, monocalcium phosphate monohydrate,hydroxyapatite, calcium deficient hydroxyapatite, fluorapatite,amorphous calcium phosphate, calcium- sodium- and potassium-phosphate,calcium- and sodium-phosphate, calcium- and potassium-phosphate, andcalcium pyrophosphate; or alternatively, b) at least a compound ofcalcium selected from the group consisting of calcium carbonate, calciumsulphate, calcium sulphate hemi hydrate, calcium oxide, and calciumhydroxide, and at least a compound of phosphate selected from phosphoricacid and all the soluble phosphates; or alternatively c) a mixture of atleast a compound defined in option a) and at least a compound defined inoption b), wherein the particle size of the calcium and/or phosphatesource is in the range of 0.05 to 100 μm.
 14. The process of claim 1,wherein the second phase comprises tetra-calcium phosphate, di-calciumphosphate or mixture thereof, wherein the ratio of tetra-calciumphosphate to di-calciumphosphate is between 1:5 and 5:1.
 15. (canceled)16. (canceled)
 17. The process of claim 1, wherein the foam furthercomprises an active agent, a viable cell, a growth factor or acombination thereof.
 18. (canceled)
 19. (canceled)
 20. The process ofclaim 1, wherein the foam sets in less than 60 min at 37° C., and theratio of the first phase to the second phase is between 10:1 and 1:10.21. (canceled)
 22. (canceled)
 23. A calcium phosphate foam comprising: acalcium phosphate cement and at least one stabilizing agent, wherein thestabilizing agent is selected from the group consisting of surfactants,gelling agents, soluble phosphate salts, organic acids, and any mixturesof the foregoing, wherein the foam has a macroporosity in the range of 5to 90 vol %, and exhibits a setting time measured by the Gillmoreneedles method or measured by a Zwick Materialtester below 45 min,wherein the foam is stable for at least 15 min.
 24. (canceled) 25.(canceled)
 26. (canceled)
 27. (canceled)
 28. (canceled)
 29. The calciumphosphate foam according to claim 23, further comprising a crosslinkingagent.
 30. A solid state structure for use in bone regeneration, tissueengineering or as a bone substitute prepared by setting or crosslinkingof the foam obtained by the process of according to claim
 1. 31.(canceled)
 32. A calcium phosphate cement foam for use in boneregeneration, tissue engineering, or as a bone substitute, prepared bythe process according to claim
 1. 33. (canceled)
 34. A bone foamapplicator, comprising: a first container for storing a firstcomposition having a first outlet; a second container for storing asecond composition having a second outlet; a mixing arrangement having afirst inlet and a second inlet, and an application outlet, an activationunit, wherein the first outlet is connected to the first inlet, and thesecond outlet is connected to the second inlet, wherein the activationunit is adapted to activate a convey of the first composition from thefirst container and the second composition from the second container tothe mixing arrangement, wherein the mixing arrangement comprises amixing volume being connected to the first inlet, the second inlet andthe application outlet, wherein the mixing volume being adapted formixing the first composition and the second composition within themixing volume for foaming the mixed first composition and secondcomposition when exiting the application outlet.
 35. The bone foamapplicator of claim 34, wherein at least one of the first container andthe second container are adapted to store a propellant for blowing outthe respective first and second composition.
 36. The bone foamapplicator of claim 34, wherein the mixing volume comprises a tubularsection having a circular cross section, and wherein the activation unitis integrally formed with the mixing arrangement and adapted to activateat least one valve positioned in the respective first and second outletof the respective first and second container.
 37. (canceled)
 38. Thebone foam applicator of claims 34, wherein the application outlet has aninner diameter of between about 0.3 and about 5.0 mm.
 39. The bone foamapplicator of claim 34, wherein the second container comprises one ormore sources for calcium and/or phosphate and the one or more sourcesfor calcium and/or phosphate are preferably selected from a) at least asource of calcium and/or phosphate selected from tetracalcium phosphate,dicalcium phosphate anhydride, dicalcium phosphate dihydrate, alphatricalcium phosphate, beta tricalcium phosphate, monocalcium phosphatemonohydrate, hydroxyapatite, calcium deficient hydroxyapatite,fluorapatite, amorphous calcium phosphate, calcium- sodium- andpotassium-phosphate, calcium- and sodium- phosphate, calcium- andpotassium-phosphate, and calcium pyrophosphate; or alternatively, b) atleast a compound of calcium selected from calcium carbonate, calciumsulphate, calcium sulphate hemi hydrate, calcium oxide, and calciumhydroxide, and at least a compound of phosphate selected from phosphoricacid and all the soluble phosphates; or alternatively c) a mixture of atleast a compound defined in option a) and at least a compound defined inoption b).